Compounds having hypocholesterolemic properties

Abstract

This invention relates to compounds which are steroidyl derivatives of 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one and the corresponding ring-opened hydroxy acid form thereof which are useful as antihypercholesterolemic agents, to pharmaceutical compositions including such compounds, and to their use in treating hypercholesterolemia.

What is claimed is: 
     
       1. A compound of the formula ##STR35## wherein: R 1  is methyl or part of a double bond; R 2  is hydrogen, alkyl, aryl or aralkyl;   R 3  is hydrogen, alkyl, or part of a double bond;   R 2  and R 3  together may form a spiro-group of formula ##STR36##  where m is 0-4; R 4  and R 5  are independently hydrogen, alkyl, aralkyl or aryl;   W is carboalkoxy, carboaryloxy, carboaralkoxy, hydrogen, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, alkylthio, alkylsulfonyl, arylthio, arylsulfonyl, alkylsulfonyl, aralkylsulfonyl, alkylsulfinyl, arylsulfinyl aralkylsulfinyl, acyloxy, aroyloxy, acylamino or aroylamino;   W' is hydrogen or part of a double bond;   W and W' together may form an oxo group provided that the A ring of the steroidyl group is not a phenyl ring and provided further that the A ring of the steroidyl group does not contain a double bond in the 2,3 or 3,4 position;   X is carboalkoxy, carboaryloxy, carboaralkoxy, hydrogen, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, alkylthio, alkylsulfonyl, arylthio, arylsulfonyl, alkylsulfonyl, aralkylsulfonyl, alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, acyloxy, aroyloxy, acylamino or aroylamino;   X' is hydrogen;   X and X' together may form an oxo group;   Y is carboalkoxy, carboaryloxy, carboaralkoxy, hydrogen, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, alkylthio, alkylsulfonyl, arylthio, arylsulfonyl, alkylsulfonyl, aralkylsulfonyl, alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, acylamino, aroylamino or ##STR37##  wherein R 6 , R 7  and R 8  are independently hydrogen, alkyl, aralkyl or aryl;   Y' is hydrogen;   Y and Y' together may form an oxo group;   Z is ##STR38##  where R a , R b , and R c  are independently hydrogen or lower alkyl; and   wherein the notation     on the ring indicates that the bond may be a single or double bond, and   n is 0 or 1.   
     
     
       2. A compound of claim 1 of the formula ##STR39## 
     
     
       3. A compound of claim 1 of the formula ##STR40## 
     
     
       4. A compound of claim 1 of the formula ##STR41## 
     
     
       5. A compound of claim 4 of the formula ##STR42## 
     
     
       6. A compound of claim 5 of the formula ##STR43## 
     
     
       7. A compound of claim 5 of the formula ##STR44## 
     
     
       8. A compound of claim 6 of the formula ##STR45## 
     
     
       9. A compound of claim 8 wherein R 2  is hydrogen, alkyl, aryl or aralkyl; and   R 3  is hydrogen, alkyl or part of a double bond.   
     
     
       10. A compound of claim 9 which is 12α-(2,2-dimethyl)butyryloxy-3α-hydroxy-17a-[E-2-(4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on-6(S)-yl)ethenyl]-D-homo-5β-androst-17-ene. 
     
     
       11. A compound of claim 9 which is 12α-(2,2-dimethyl)butyryloxy-3α-hydroxy-17β-[3-(4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on-6(R)-yl)-2(R)-2-propyl]-5β-androstane. 
     
     
       12. A compound of claim 9 which is 7α-acetoxy-12α-(2,2-dimethyl)butyryloxy-3α-hydroxy-17.beta.-[3-(4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on-6(R)-yl)-2(R)-2-propyl]-5β-androstane. 
     
     
       13. A compound of claim 9 which is 12α-(2,2-dimethyl)butyryloxy-3α-hydroxy-17β-[3-(4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on-6(R)-yl)-2(R)-2-propyl]-5β-androst-8(14)ene. 
     
     
       14. A compound of claim 9 which is 12α-(2,2-dimethyl)butyryloxy-3α-hydroxy-17β-[2-(4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on-6(R)-yl)-ethyl]-5β-androst-8(14)-ene. 
     
     
       15. A compound of claim 2 which is 12α-(2,2-dimethyl)butyryloxy-3α-hydroxy-17β-[3-(4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on-6(R)-yl)-2(R)-2-propyl]androst-1,3,5(10)-triene. 
     
     
       16. A compound of claim 3 which is 12α-(2,2-dimethyl)butyryloxy-3α-hydroxy-17β-[2-(4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on-6(R)-yl)-ethyl]androst-5(6)-ene. 
     
     
       17. A compound of claim 7 which is 12α-(2,2-dimethyl)butyryloxy-3α-hydroxy-17β-[2-(4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on-6(R)-yl)-ethyl]-5α-androst-8(14)-ene. 
     
     
       18. A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 
     
     
       19. A method of inhibiting cholesterol biosynthesis in a patient in need of such treatment comprising administering a pharmaceutical composition defined in claim 18.